A review of the physiology behind letrozole applications in infertility: are current protocols optimal?
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REVIEW
A review of the physiology behind letrozole applications in infertility: are current protocols optimal? Bruce I. Rose 1,2
&
Samuel E. Brown 1,2,3,4
Received: 11 June 2020 / Accepted: 13 July 2020 # The Author(s) 2020
Abstract Letrozole is a targeted aromatase inhibitor which has primarily been used in post-menopausal women with breast cancer. Recently, it has been utilized in infertile pre-menopausal women because of its ability to enhance FSH production for ovulation induction. However, the ovarian follicle’s response to FSH is only a part of the endocrine events occurring in a developing follicle. The health of the small antral follicles is driven primarily by androgens, which contribute to granulosa cell mitosis, sensitivity to FSH, and resistance to atresia. In contrast, elevated androgens in the late antral to pre-ovulatory follicle have a negative impact on follicle health and lead to atresia and cystic follicle formation. This ovarian physiologic data suggests that current applications of letrozole to infertility may be squandering some of the primary benefits available in using letrozole to promote follicle development. Four applications of letrozole to infertility that have appeared in the medical literature are reviewed. Androgen-related benefits are reviewed and various questions put forward about how letrozole could be more effectively used to help patients in these settings. Keywords Letrozole . Aromatase inhibitor . Androgens . Ovarian physiology . Ovulation induction . Fertility preservation . Diminished ovarian reserve . In vitro maturation . IVM
Introduction and background Letrozole has been used with increasing frequency in infertility therapy. Letrozole blocks the conversion of C-19 androgens to C-18 estrogens by competitively inhibiting the enzyme, aromatase (cytochrome P-450 19), which is an essential step in estrogen biosynthesis in the ovary and other tissues. The use of letrozole results in increased androgens and decreased estrogens in tissues throughout the body [1, 2]. Letrozole has proven to be a valuable drug in the treatment
* Bruce I. Rose [email protected] 1
Brown Fertility, 8149 Point Meadows Way, Jacksonville, FL 32256, USA
2
Department of Obstetrics and Gynecology, School of Medicine, University of Central Florida, Orlando, FL 32816, USA
3
Department of Obstetrics and Gynecology, School of Medicine, University of Florida, Jacksonville, FL 32209, USA
4
School of Medicine and Science, Department of Obstetrics and Gynecology, Mayo Clinic, FL 32224 Jacksonville, USA
of estrogen receptor–positive breast cancers which constitute about two-thirds of all breast cancers [3, 4]. In this mini-review, we examine four applications of letrozole to treat infertility that have appeared in the medical literature. The focus of this review is on how these therapies utilize the pharmacological properties and physiological ovarian consequences of letrozole. The initial use of letrozole in infertility mimics the long-term use of clomiphene citrate in infertility therapy. Clomi
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